In the medical and surgical fields, there has been an unmet need for compositions with handling characteristics that range from a viscous oil to a hard wax. Desirable compositions would have one or more of the following properties: biocompatibility, non-metabolizable under physiological conditions, low toxicity and corrosiveness, readily eliminated from the body in unmodified form, easy and inexpensive to manufacture and store, long lived, and variable viscosity and hardness. Preferably, such compositions would be resorbed and readily eliminated by the body after they had served their intended purpose.
Such compositions would have a wide range of uses. For uses in the surgical field, compositions which have handling characteristics resembling a hard, adherent wax could be useful as a hemostatic agent that could be used to prevent bleeding from the surfaces of bones. Compositions with oily, greasy, or waxy characteristics (in ascending degrees of hardness) can be used as lubricants of surgical instruments and implants. Applications would include use as a carrier or excipient for particulate implantable materials, bioactive agents, and other pharmaceutical agents. The compositions are also suitable as a matrix for particulate material, adhesive/cohesive, filler, and/or lubricant; they may also be used as dispersing or suspending agents, emulsifiers, extenders, thickeners, and/or bodying agents for compositions, in particular for cosmetic and pharmaceutical formulations.
Until our discovery, there were no biocompatible, substantially non-toxic, water-soluble compositions available with handling characteristics that range from a grease to a wax over a temperature range from about 25° C. to about 37° C. for medical and surgical applications, which can be formulated to be substantially free of water (e.g., less than about 5% or about 1% water). All previously known water-soluble compositions with such handling characteristics and intended for medical or surgical applications contained water in their formulation.
Currently, the medical and surgical need for the appropriate formulations is being met in a number of different and less than acceptable ways. Most have the problem of either not being completely biocompatible or not having handling characteristics that are well suited for their intended application. Beeswax, commonly used as a bone hemostatic agent, is non-resorbable, interferes with bone healing, and causes inflammatory reactions. Compounds derived from biological sources, such as collagen, have the potential to cause immune reactions and may even have the potential to spread infectious agents. Many compounds in use fall into the category of hydrogels. Hydrogels consist of a three dimensional network of hydrophilic polymer chains in an aqueous medium that are cross-linked through either chemical or physical bonding. Theoretically, at least, the network is infinite and the polymer chains are effectively a single molecule. By definition hydrogels contain at least 10% water by total weight (or volume); but more commonly contain 10 to 50 times more water than polymer (w/w/ or w/v). Hydrogels in general do not have ideal physical characteristics for a material that needs to be handled and manipulated into position. They are typically elastic but not plastic, lacking malleability and ductility, and are often labile when exposed to compressive, tensile or shearing forces, leading to irreversible fracturing or tearing of the material. The water within hydrogels also may affect the lifetime of bioactive agents. Hydrocarbon compounds, either petroleum based (e.g., paraffin, petrolatum) or from other sources such as beeswax or plant-derived waxes, have the appropriate handling characteristics, but are not water soluble. Silicon oils and silicon gels are neither biologically inert nor water soluble. Thus, suitable polymers for therapeutic use remain to be discovered.
In the fields of surgery and dentistry, there is a need for an implantable material that contains a particulate component that can serve as a framework for tissue ingrowth. The particulate component can be selected from a broad range of natural and synthetic implantable substances, including but not limited to native autogenous bone or cartilage, bone or cartilage from other sources that is either grafted directly or after processing, collagen, hydroxyapatite, polymethylmethacrylate (PMMA), polytetrofluoroethylene (PTFE), polyethylene, and dimethylpolysiloxane.
The performance of particulate implants is markedly improved by the addition of a matrix to temporarily adhere the particles to one another and to form a putty that serves to improve the handling characteristics and acts as a delivery system. The majority of matrices in use or disclosed in the prior art are aqueous solutions or hydrogels including collagen, glycerol, polysaccharides, mucopolysaccharides, hyaluronic acid, plasdones, and polyvinylpyrrolidones (PVP).
Collagen, in the form of gelatin, has been used in ARTEPLAST® from Rofil Medical International. It is an injectable material comprised of microspheres of PMMA suspended in a gelatin solution. Following implantation, the gelatin is resorbed and replaced by native collagen. Another formulation, ARTECOLL® is a product currently available in Europe and Canada. It is comprised of smooth PMMA spheres, suspended in bovine collagen from a closed pharmaceutical herd at a concentration of 25% PMMA/75% collagen, by weight with 0.3% lidocaine. Because ARTECOLL® contains bovine collagen, testing for allergy to such collagen is recommended. Bovine collagen carries the risk of an immunogenic reaction by the recipient patient. Recently, it has been found that a disease of cattle, bovine spongiform encephalopathy (BSE) is transmitted from bovine tissue to humans. Thus, bovine collagen carries a risk of disease transmission and is not a desirable matrix for allograft bone. Human collagen is free of these animal-based diseases. However, collagen absorbs slowly in the human body, particularly in a bony site with a low degree of vascularity.
Glycerol is used as a matrix for demineralized allograft bone in the form of a gel. For example, GRAFTON from Osteotech is a simple mixture of glycerol and lyophilized, demineralized bone powder (U.S. Pat. No. 5,073,373). GRAFTON works well to allow the surgeon to place the allograft bone at the site. But glycerol has a very low molecular weight (92 daltons) and is very soluble in water, the primary component of the blood which flows at the surgical site. Glycerol also experiences a marked reduction in viscosity when its temperature rises from room temperature (typically 22° C. in an operating room) to the patient's body temperature (typically 37° C.). This combination of high water solubility and reduced viscosity causes the allograft bone with a glycerol matrix to be runny and to flow away from the site almost immediately after placement. This prevents the proper retention of the allograft bone within the site as carefully placed by the surgeon. The use of the low molecular weight glycerol carrier also requires a high concentration of glycerol to be used to achieve the bulk viscosity. Glycerol and other low molecular weight organic solvents are also toxic and irritating to the surrounding tissues. U.S. Pat. No. 6,306,418 describes the use of glycerol as the matrix for TEFLON particles in the field of urology.
Surgical implantation of artificial sphincters has often been employed to treat patients suffering from urinary incontinence. The most common and widely used method to treat patients with urinary incontinence is periurethral injection of a composition commercially sold as POLYTEF, which is a paste comprising a 1:1 by weight mixture of glycerin matrix and TEFLON particles. After injection, however, the glycerin is readily dissipated into the body over a period of time and then metabolized or eliminated, leaving only the TEFLON particles. A drawback of such a paste is that the size of the particles is sufficiently small so as to allow them to migrate to other locations of the body such as the lungs, brain, etc. TEFLON particles have been known to induce tissue reaction and form TEFLON-induced granulomas in certain individuals. This tissue reaction to TEFLON also has caused concerns for the patient's health.
U.S. Pat. No. 4,191,747 discloses a bone defect treatment with denatured bone meal freed from fat and ground into powder. The bone meal is mixed with a polysaccharide in a solution of saline and applied to the bone defect site.
U.S. Pat. No. 5,290,558 discloses a flowable, demineralized bone powder composition using an osteogenic bone powder mixed with a low molecular weight polyhydroxy compound possessing from 2 carbons to about 18 carbons including a number of classes of different sugars such as monosaccharides, disaccharides, water-dispersible oligosaccharides, and polysaccharides.
U.S. Pat. No. 5,356,629 discloses making a rigid gel in the form of a bone cement to fill defects in bone by mixing biocompatible particles preferably PMMA coated with polyhydroxyethylmethacrylate in a matrix (e.g., hyaluronic acid) to obtain a molded semi-solid mass which can be suitably worked for implantation into bone. The hyaluronic acid can also be utilized in monomeric form or in polymeric form preferably having a molecular weight not greater than about one million daltons. It is noted that non-bioabsorbable but biocompatible particles can be derived from xenograft bone, homologous bone, autogenous bone, as well as other substances. The bioactive substance can also be an osteogenic agent such as demineralized bone powder, in addition to morselized cancellous bone, aspirated bone marrow, and other autogenous bone sources. This is a cement used for implantation of hip prosthesis.
Ersek et al. describe the clinical use of soft particles delivered as a biphasic hydrogel material (Plast. Reconstr. Surg. 95:985-992, 1995). The material comprises solid particles of dimethylpolysiloxane ranging in size from 100 micron to 600 micron suspended in a hydrogel of the plasdone family.
BIOPLASTIQUE® material from Uroplasty, a biphasic material, consists of solid silicone particles, ranging from 100 microns to 400 microns in size, suspended in PVP. But this material elicits a low-grade inflammatory response upon injection. In a rabbit model, the hydrogel matrix is reabsorbed by the body within 96 hours and eliminated in an intact form by the kidneys. The hydrogel matrix is replaced by fibrin and inflammatory cells. Fibroblasts are recruited into the area by 14 days and begin to replace the fibrin bed with a collagen matrix. The collagen encapsulates and localizes the silicone, and animal studies have not shown any evidence of foreign body migration. Deposition of collagen progresses, replacing the organic component of the material in a ratio slightly greater than 1:1. Connective tissue cells develop and replace about 30% of the matrix with host collagen fibrils. At 382 days, fibrosis was complete and each individual particle appeared to be encased in its own fibrous capsule. This material has the distinct disadvantage of using silicone, which may be of concern when evaluating long-term safety.
U.S. Pat. No. 5,641,502 discloses a material comprising (i) a polymer derived from hydroxyacids, tactones, carbonates, etheresters, anhydrides, orthoesters, and copolymers, terpolymers and/or blends thereof and blended with (ii) at least one surface active agent which is from 2% to 55% by weight block copolymer of polyoxyethylene and polyoxypropylene. Additional, a leaching agent from 0% to 70% by weight may be included in the blend to provide a porous microstructure.
Poloxamer-based thermoreversible hydrogels are being developed for use as a drug delivery system. The cooled poloxamer solution containing the drug is liquid at less than 10° C. It is easily administered to the desired location in the body and the drug-containing solution forms a hydrogel as it warms to 37° C. The solidified gel remains at the site, slowly releasing the drug by diffusion and/or gradual solubilization of the gel matrix. Such compositions are distinguished from our invention because they do not include a random copolymer component, and do not have the wide variety of utilities disclosed herein.
U.S. Pat. No. 6,281,195 discloses a poloxamer hydrogel matrix for the delivery of osteogenic proteins. In particular, poloxamer 407 (PLURONIC® F127) is used in the form of a hydrogel. But hydrogels have disadvantages if used as the matrix instead of the present composition.
Therefore, in the field of surgery, a biocompatible, substantially non-toxic composition with adhesive and cohesive properties is needed. Hemostasis is an example of an application of such a composition. Bone is a structure with a rich blood supply. Blood within bone typically circulates through a system of canals and within the bone marrow and, as such, hemostasis using traditional methods, such as an electrocautery, is ineffective. Traditionally, bone hemostasis is obtained by applying a formulation primarily composed of beeswax onto the cut surface of the bleeding bone. The beeswax adheres to the bone and serves to act as a tamponade of the canals and bone marrow space, eventually leading to the clotting of the blood. Unfortunately, beeswax is not cleared by the body and acts to interfere with bone healing and inflammatory reactions are known.
Provisional U.S. Appln. No. 60/162,347 discloses a water-soluble wax for use as a bone hemostasis agent whose handling characteristics aim to simulate those of beeswax. The application of alkylene oxide block copolymers over the bleeding sites of the bone for hemostasis was described. Advantages over prior art methods include the finding that bone growth was not inhibited, and the water-soluble composition was resorbed and excreted. The preferred material described is a 9:1 blend by weight of two block copolymers: poloxamer 235 (PLURONIC® P85) and poloxamer 238 (PLURONIC® F88). But a random copolymer component was neither taught nor suggested. Blending poloxamer 235 and poloxamer 238 requires a precise combination of ingredients and snap cooling to preserve the blend, which is not a readily static mixture, and obtain the desired mechanical properties.
The formulations of bone hemostasis agents in the prior art lack one or more of the following attributes: biocompatibility, superior handling characteristics, and easy manufacture and storage. In contrast, preferred embodiments of the invention provide a biocompatible, substantially non-toxic, stable (i.e., non-metabolizable and readily eliminated) composition with superior handling characteristics.
It is an objective of the invention to provide a composition with superior properties for medical and surgical applications. Biocompatibility, substantial non-toxicity, water solubility, desirable handling properties (e.g., hardness, ductility, malleability), emulsification, filling, slipperiness (e.g., lubrication), surface activity (e.g., surface activity), tackiness (e.g., adhesion, cohesion), and thickening are characteristics of particular interest. Further advantages of the invention are described.